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Antidepressants, anxiolytics, psychostimulants, psychodysleptics
Ján Mojžiš
P.J. Šafárik University
Faculty of Medicine
Department of Pharmacology
Košice
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Antidepressants
Definitions
Affective disorders - mental illnesses characterized by pathological changes in mood (not thought – compare with schizophrenia)
1. Unipolar disorders Depression – pathologically depressed mood (life
time prevalence up to 17%)
Mania – excessive elation and accelerated psychomotoric activity (rare)
2. Bipolar disorder (manic-depressive illness) –„cycling mood“ = severe highs (mania, event. hypomania) and lows
(major depressive episodes)
prevalence 1-5%, life-time illness, stronger genetic background
3MBP
Depression
Depression afflicts approximately 5% - 10 %of the population, 1-2% with bipolar disorder.
Suicide from depression is 25-30% of depressed population.
Depression 2-3 X higher in women.
70% of patients have response to drugs.
Clinical symptoms of depression
loss of pleasure (anhedonia)
loss of energy
social withdrawal psychomotor retardation or agitation
insomnia
loss of appetite
decreased hygiene
crying spells
difficulty
concentrating
sad
thoughts/thoughts
of suicide
hopelessness
helplessness
guilt/shame
Biological Theories
Disordered genes predispose people
to depression or bipolar disorder
Genetic TheoryNeurotransmitter
theories
Dysregulation of neurotransmitters
and their receptors
Neuroendocrine abnormalities
Altered brain-wave activities
affect mood
Chronic hyperactivity in the
hypothalamic-pituitary-adrenal axis
and slow return to baseline after
stressor affect the functioning of
neurotransmitters.
Neurophysiological
abnormalities
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first great theory - role of monoamine
neurotransmitters (NE, 5-HT)
defficiency of neurotransmitters –
depression
simplistic theory
SEROTONIN - A key player
Serotonin has widespread distribution and density of innervation in CNS (mood, memory, pleasure, aggression, hypothalamic control)
Alterations of serotonin in depressed drug-free patients: The reduction point of view
decreased 5-HT levels in CSF
increased amounts of 5-HT2 receptors in brain
reduced levels of plasma tryptophan
Cont.
blunted neuroendocrine responses to the serotonin releasing drug fenfluramine
efficacy of SSRI’s in treating depression
loss of SSRI efficacy with tryptophan depletion
Increased presynaptic 2 noradrenergic receptor sensitivity=greater reduction in 5-HT release
problem - timming of antidepressant effect
on neurotransmitts is far from the timing of
the antidepressant effect on mood
newer theories - role of neurotransmitter
receptors
disturbancies in signal transducion
The purpose of antidepressants is
the increase the neurotransmitters
in the synapse
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MAO inhibitors (IMAO)
first antidepressive agents used clinically
"clasical" (e.g. tranylcypromine) irreverzible,
nonselective inhibition of MAO-A and MAO-B
for antidepressive effects - inhibition of MAO-A
2-3 weeks for antidepressive action
use of "clasical" MAOI is now limited - side
effects, interactions (food, drugs)
tyramine (chees, red wine, beer) is normally
inactivated by MAO-B in the gut
tyramine causes release of stored atecholamines
tachycardia, hypertension,
headache, cardiac arrhythmias
patients must avoid tyramine-containing foods
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RIMA (Reversible Inhibitors of MAO-A)
Moclobemide
reversible inhibition of MAO-A
inhibition of deamination of 5-HT, NE, D
PK
good absorption in GIT
50% bound to plasma albumine
95% excreted in urine as an inactive metabolites
Side effects
insomnia, nausea, headache, dizziness, desorientation, nervousness
effect on CVS in combination with tyramine - less important
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Tricyclic antidepresants (TCA)
many years drug of choice
inhibition of re-uptake increase of NE, 5-HT
also blockade of M, H1 1 receptors
2-3 weeks for antidepressive action
M-receptors dry mouth, urine retention,
constipation, blurred vision
M+1-receptors - tachycardia, hypertension,
postural hypotension,
H1-receptors sedative effects, body weight gain
MECHANISM OF
ACTION
Pharmacological properties:
Therapeutic effect• Block presynaptic NE reuptake
transporter
• Block presynaptic 5-HT
reuptake transporter
Side effectsTCAs block other receptors:
• Muscarinic
• α1
• Histamine 1
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TCA – cont.
Imipramine
antidepressine effect after one week therapy
for long ter effect - 3 or more weeks of application
PK
good absorption from GIT
90% bound to albumine
main metabolite desipramine biologically active
excreted by urine as a glucuronide
Side effects
dry mouth, urine retention, constipation, blurred vision
tachycardia, hypertension, postural hypotension,
insomnia, anorexia, hallucination
TCA TOXICITIES
lowers threshold for convulsions
cardiac arrhythmias
cardiac conduction defects
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Selective Serotonin Reuptake Inhibitors (SSRI)
most common prescribed antidepressants today
inhibiion of 5-HT re-uptake
increase of 5-HT effect on postsynaptic 5-HT and 5-HT1A
presynaptic receptors
stimulation of 5-HT1A receptors „down-regulation“ lower
effect on 5-HT release from presynaptic neurons
inhibition of NE reuptake
blockade of 1, H1 alebo M- receptors cardotoxic,
hypotensive, sedative effects
MECHANISM OF ACTION
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SIDE effects of SSRI’s
nausea, GI disturbances
headache
nervousness
insomnia
some sedation
anorgasmia/impotence
possible fatal interaction with MAOI’s
Serotonin syndrome
A potentially fatal interaction when SSRI’s
and MAOI’s are combined
Symptoms: autonomic instability (labile HR/BP)
hyperthermia
rigidity and myoclonus
confusion,delirium
seizures
coma
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SSRI – cont.
Fluoxetine
in depresion of different etiology
PK
food prolongs time of absorpion
95% to plasma albumine
metabolised in the liver major metabolite (norfluoxetine) simmilar effect as a fluoxetine
Side effects
lower incidence and intensity
GIT - nausea, anorexia,
CNS - insomnia, tremor, headache, vertigo
CVS - orthostatic hypotension
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SSRI – cont.
Citalopram
high selective for 5-HT
no affinity to M, H1 a 1 receptors
depression, panic fear, bulimia, anorexia nervosa
PK
bioavailabity - 80%,
bound to albumine - 80%
metabolised in the liver, no of metabolits has effect as a parent drug
excreted via kidney
Side effects
nausea, insomnia, in man - sexual disturbancies
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SSRI – cont.
Fluvoxamine
bioavailability cca 53%
other as a citalopram
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Newer antidepressants
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Norepinephrine Reuptake Inhibitors (NRI)
Reboxetine
introduced in 1997
inhibition of NE re-uptake
minimal effect on 5-HT a D
depression, narcolepsy, panic fear
98% bound to 1 acid glycoproteine
Side effects
well tolerated
obstipation, dry mouth, urine retention, insomnia, tachycardia
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Norepinephrine and Dopamine Reuptake Inhibitors
(NDRI)
Bupropion
weak inhibitor of D and NE re-uptake
major metabolite - strong NE re-uptake inhibitor
suitable for patients with intolerability or low response to SSRI
suitable to supress withdrawal symptoms in nicotine-
dependent people
contraindicated in epileptic patients - proconvulsive effect
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Serotonin and Norepinephrine Reuptake Inhibitors
(SNRI)
action similar to TCA - NE and 5-HT re-uptake inhibition
no effects on M, H1 and 1-adrenergic receptors
Venlafaxine
low doses 5-HT, moderate doses NA, high doses D
metabolised in the liver - O-desmethylvenfalaxine - active
metabolit
Side effects
nausea, constipation, somnolece, nervousness, headache
serotonine syndrome
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Noradrenergic and Specific Serotoninergic
Antidepressants (NaSSA)
blockade of presynaptic 2-receptors
2-adrenergic autoreceptors regulation
of NE release
2-adrenergic heteroreceptors (on
serotoninergic neurons) regulation of 5-
HT release
blockade of 2-receptorov release of
NE a 5-HT
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NaSSA – cont.
Mirtazapine
high affinity to 2-receptors
antagonist of 5-HT2, a 5-HT3 and H1-receptors
Side effects
somnolence, dry mouth, increase of apetite, body weight gain, constipation, serotonine syndrome
Mianserine
selective antagonist of presynaptic 2-adrenergic receptors
partial effect on 1, 5-HT2, 5-HT3 and H1-receptors
main metabolites biological activity
Side effects
hypersensitivity, nausea, tremor
Mania
Symptoms of mania
increased energy (buying, phoning, sex)
pressured speech, talkativeness
decreased sleep
drunkenness
combative, dangerous behavior
racing thoughts
impulsive actions
and decisions
elevated mood
euphoria
grandiosity
irritability/hostility
(easily angered)
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Anti-manic therapy
Lithium
used more than 50 years
mechanism of action ?
Possible mechanism is the reduction of neuronal
PI second messenger resulting in reduced
response of neurons to ACh and NE
Clinical pharmacology
primary therapy for mania
a narrow therapeutic window
absolutely necessary to monitor serum level (trough level approx. 5 days after initial dose)
solely eliminated by kidney, therefore assess
patient’s kidney function
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Lithium – cont.
Side effects
intensity depends on plasma concentration
first days of therapy tremor of hands, urination, nausea,
thirst
first signs of intoxication vomiting, diarrhea, muscle
weaknes, loss of coordination
higher doses tinitus, blurred vision, polyuria
plasmatic concentration over 3,0 mmol.l-1
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Lithium – cont.
CNS: tremor, convulsions, epileptiformic seizures, urine and
feces incontinence, tinitus, halucination
CVS: dysrhytmias, hypotension, periferal circulatory colaps,
bradycardia
GIT: anorexia, nausea, vomiting, diarrhea, gastritis, abdominal
pain,
Urogenital tract: glycosuria, albuminuria, polyuria
Skin: acne, psoriasis, pruritus, skin ulcus, angioedema,
alopecia
Other: blurred vision, dry mouthh, loss of body weight,
leucocytosis, headache, fever
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Lithium – cont.
Warnings
renal or cardiovascular diseases,
dehydratation, hyponatremia increase risk
of toxicity
water 2-3 l/day is recomended
suspect teratogen
Other medications
Anticonvulsants: carbamazepine and valproic
acid for rapid cyclers
Olanzapine approved for treatment of mania
St. John’s Wort: questionable efficacy, but high
potential for drug-drug interactions
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Anxiolytics(antianxiety drugs)
What is anxiety ?
Physical and emotional distress which
interfere with normal life.
Common emotional symptoms of anxiety
irrational and excessive fear and worry
irritability
restlessness
trouble concentrating
feeling tense
Common physical symptoms of anxiety
sweating
tachycardia
stomach upset
shortness of breath
frequent urination or diarrhea
sleep disturbances (insomnia)
fatigue
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Benzodiazepines (BDZ)
5-HT drugs
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Mechanism of action
BDZ receptor linked to GABA-A receptor complex
(bound to Cl- channels)
GABA: an inhibitory neurotransmitter
BDZ enhance GABA effect
open Cl- channels in response to GABA activation
hyperpolarization, decreased neuronal firing
Effects: antianxiety, sedative, hypnotic, anticonvulsant,
muscle-relaxant
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BDZ receptors
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BZD: Pharmacokinetics
fast cross BBB: rapid onset of action
biotransformation and half-life:
hepatic oxidation: long-t1/2, active
metabolites
glucuronidation: short-t1/2, no active metab.
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BZD: Adverse Effects
sedation, CNS depression
worse if combined with Etoh
behavioral disinhibition
irritab, excitement, aggression (<1%),
psychomotor & cognitive impairment
coordination, attention (driving)
ataxia, confusion
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BZD: Adverse Effects
Overdose: Rare fatalities if BZD alone
Severe CNS and Respiratory Depression if
combined with:
alcohol
barbiturates
narcotics
TCA
flumazenil
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BZD: Withdrawal
worse if stop abruptly
symptoms
diaphoresis, pulse, BP
tremor, lethargy, dizziness, headaches
restlessness, insomnia, irritability, anxiety
depersonalization, perceptual disturbances
also: depression, tinnitus, delirium, panic, hallucinations,
abnormal muscular movs.
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5-HT1A agonists
Buspirone
has strong anxiolytic properties
almost no sedative effect, drowsiness or hypnosis
minimal amnesia and dementia
does not potentiate other sedatives
no abuse potential
it is a weak 5-HT agonist
has both antianxiety and antidepressant effects
metabolized very quickly, grapefruit juice increases effect
slow onset of action
Uses of buspirone
as anxiolytic in mild anxiety & generalized
anxiety disorders.
not effective in severe anxiety/panic disorder.
Beta Blockers
propranolol – atenolol
act by blocking peripheral sympathetic system.
reduce somatic symptoms of anxiety.
decrease BP & slow HR.
used in social phobia.
are less effective for other forms of anxiety
TCA
Doxepin- imipramine
act by reducing uptake of 5HT & NA.
used for anxiety especially associated with
depression.
effective for panic attacks.
delayed onset of action (weeks).
dry mouth, postural hypotension, sexual
dysfunction, weight gain.
Conclusion of anxiolytics
Classes of anxiolytics USES
Benzodiazepines Generalized anxiety disorders, OCD,
phobia, panic attack
SSRIs
(Fluoxetine)
Generalized anxiety disorders, OCD,
phobia, panic attack
Tricyclic antidepressants
(doxepin, imipramine )
anxiety with depression.
panic attacks
5HT1A agonists
(Buspirone)
Mild anxiety
Not effective in panic attack
Beta blockers
(propranolol, atenolol)
Phobia (social Phobia)
MAO inhibitors
phenelzine
Panic attack, phobia
Conclusion of anxiolytics
Classes of anxiolytics Adverse effects
Benzodiazepines Ataxia, confusion, dependence,
tolerance, withdrawal symptoms,
SSRIs
(Fluoxetine)
weight gain, sexual dysfunction
Dry mouth
Tricyclic antidepressants
(doxepin, imipramine )
weight gain, sexual dysfunction,
atropine like actions
5HT1A agonists
(Buspirone)
Minimal adverse effects
Beta blockers
(propranolol, atenolol)
Hypotension
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PSYCHOSTIMULANTS
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Effects
behavioral manifestations of CNS
stimulation
mild elevation in alertness, decrease in
drowsiness and lessening of fatigue
(analeptic effect)
increased nervousness and anxiety -
convulsions.
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Methylxantines
Caffeine:
Coffee (100-150 mg/cup)
Tea (30-40 mg/cup)
Cocoa (15-18mg/cup)
Theophylline: Tea and cocoa
Theobromine: Cocoa
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Mechanisms of action
Increase cyclic nucleotide concentration –
PDE inibition
Blocks adenosine receptors
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Caffeine
commonly found in coffee, tea, soft drinks,
chocolate and a wide variety of over-the-
counter medications
it is legal to buy and easily accessible
coffeine is a physically addictive drug
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Pharmacological activity/adverse effects
Low Doses: 50-250mg/caffeine (oral doses) -
increase mental alertness, decrease drowsiness
lessen fatigue
Larger Doses: 250-600mg/caffeine - irritability,
restlessness, tremor, insomnia, headache,
palpitations
Large Doses: > 1000 mg - excitement, delirium
and clonic seizures
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CVS: Increase rate and force of the heart by
directly stimulating myocardium (low doses)
Tachycardia and arrhythmias at higher doses.
Peripheral vasodilation - decrease blood
pressure (acute administration)
Hypotension and cardiac arrest (rapid i.v.
theophyline)
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Smooth Muscles: relaxes vascular smooth
muscle (theophylline > caffeine)
Kidney: all xanthines are capable of producing
some degree of diuresis in humans (theophylline
> caffeine)
Miscellaneous: xanthines shorten clotting time
by increasing tissue prothrombin and factor V.
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Adverse effects
stimulate gastric secretions in patients with ulcer
dehydration in children due to vomiting and transient
diuretic action (theophyline)
allergic reaction (aminophylline)
psychic dependence (caffeine)
high doses
emesis, convulsion,
lethal dose is about 10 g (about 100 cups of coffee) -
induces arrhytmias
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Therapeutic uses
caffeine + plus ergot alkaloid (ergotamine):
used to treat migraine headaches
theophylline:
prophylaxis for chronic asthma
respiratory stimulant
bronchodilator for relief of asthmatic symptoms
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Psychomotor stimulants
Drugs of primary importance
Amphetamine - prototype
Methamphetamine
Methylphenidate
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Characteristics
all compounds are absorbed well orally
large portion of untransformed amphetamine is excreted
unchanged in the urine
acidifying the urine with ammonium chloride hastens its
clearance, and thus reduces its reabsorption in the renal
tubules.
overdose: hyperreflexia, tremors and convulsions
fatalities: hyperthermia rather than cardiovascular effects
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Pharmacological actions
the primary effects of an oral dose are:
wakefulness, alertness, decrease fatigue
mood elevation, increased ability to concentrate
an increase in motor and speech activity
amphetamines also diminish the awareness of
fatigue - person may push exertion to the point of
severe damage or even death.
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stimulate the respiratory center, especially when
respiration is depressed by centrally acting
drugs, (barbiturates and alcohol)
amphetamine can reverse the marked sedation
and behavioral retardation resulting from
reserpine-like drug
depresses appetite by their action on the lateral
hypothalamus rather than an effect on metabolic
rate
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Mechanisms of action
releases monoamines at synapses in the brain
and spinal cord
inhibits neuronal uptake of monoamine
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Therapeutic uses
methylphenidate
attention-deficit hyperactivity disorder (ADHD)
narcolepsy - amphetamine or methylphenidate
fenfluramine
obesity – withdrawn due to cardiotoxicity /hypertension, cardiac
fibrosis
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Adverse effects
CNS: euphoria, dizziness, tremor, irritability,
insomnia, convulsion (at higher doses),
hyperthermia and coma
CVS: cardiac stimulation leads to headache,
palpitations, cardiac arrhythmias, anginal pain
other: weight loss, psychotic reaction which are
often misdiagnosed as schizophrenia.
addiction - including psychical dependence,
tolerance and physical dependence.
Hallucinogens
Definitions
“Substances that create gross distortions in
perception without causing loss of
consciousness when administered in low
doses.”
“Substances that alter sensory processing in
the brain, causing perceptual disturbances,
changes in thought processing, and
depersonalization.”
Hallucinogens …
Are found naturally in plants and can be
produced synthetically.
Resemble 1 of 4 neurotransmittersAcetylcholine
Catecholamines (Norepinephrine & Dopamine)
Serotonin
Common Hallucinogenic Effects
1) Alterations in time and
space perception
2) Changes in self-
awareness
3) Increase sensitivity to
textures, shapes, tastes,
and sounds
4) Visual disturbances (i.e.
flashes of light or
kaleidoscope-like
patterns)
5) Hallucinations
6) Feelings of
enlightenment or
spiritual awakening
Categories of Hallucinogens
1) Anticholinergic
2) Catecholamine-like
3) Serotonin-like
4) Psychedelic anesthetics
Attach to AhC (Impairs learning and memory as result)
Found in Belladonna, Nightshade, Mandrake
plants
Effects: Dry mouth, sweating, dry skin, body
temperature, blurred vision, heart rate, dilated
pupils, drowsiness, attention.
High Doses = Hallucinations, paralysis of
respiratory system, coma, and death.
Examples: scopolamine, mandrake, hyoscine,
hyoscyamine, and atropine.
Anticholinergic Hallucinogens
Mescaline
Myristin
Elemicin
Synthetic Amphetamine Derivatives
Catecholamine-Like Hallucinogens
MDMA
Street Names: Adam,
Ecstasy, X, E, XTC, Blue
Kisses, E bombs, Happy
Pill, Smurfs, Wafers, &
others
More psychedelic than
MDMA
Synthesized in 1912
Schedule 1 Drug in 1985
Effects similar to MDA
Pharmacodynamics:
Increases levels of
Norepinephrine,
dopamine, & serotonin
released.
MDMA Effects
Hallucinogenic Effects: distortions in time &
perception.
Stimulant Effects: Euphoria & hyperactivity,
increase blood pressure & heart rate
MDMA…The Negative Effects
Psychological: depression, severe anxiety, paranoia, and sleep disturbances.
Physical: muscle tension, nausea, blurred vision, rapid eye movements,
High doses: sharp increase in body temperature, muscle breakdown, and kidney & cardiovascular system failure.
These effect also happen at low doses in combination with intense exercise or acitivity.
Long-Term: liver damage & brain damage.Brain damage due to destruction of serotonin producing neurons = therefore
problems regulating mood, pain, sleep, and aggression can result.
LSD
Psilocybin
Psilocin
DMT
Bufotenine
Ololiuqui
Harmine
Serotonin-like Hallucinogens
LSD
Street names
Acid, Battery Acid, Pane, Brown Bombers, Coffee,
Crystal Tea, Dots, Golden Dragon, Haze, Looney
Toons, Microdot, Lucy, Paper Acid, Pearly Gates,
Pink Panther, Rainbow, Superman, White
Lightening, Window Glass, Yin Yang, Zen, Yellow
Sunshine, Sugar Cubes, & others.
Derived from ergot alkaloids of the rye fungus.
Colorless, odorless, bitter taste.
Most potent mood & perception altering drug (can cause effects at 25 μg = in weight to a few grains of salt).
Was used to treat alcoholism, paranoia, schizophrenia, and autism.
Pharmacodynamics
Binds to 5-HT2 serotonin receptors
Effects due to disruption of raphe nuclei (pons/medulla), which filters incoming sensory stimuli, creating surge of sensory information and overload of brain circuits.
Effects cerebral cortex (involved in mood, cognition, and perception) & locus ceruleus (receives sensory info)
Effects
Dilation of pupils, dizziness, dreamy detached feelings, changes in time perception, color/smells/sounds intensified, increase heart rate & blood pressure, sweating, dry mouth, hallucinations.
At High doses causes nausea, tremors, & confusion.
Moods typically depends on mood prior to use, causing those to become intensified.
However, moods can change quickly from euphoria to terror and panic.